Diastereoselective, Vinylogous Mukaiyama Aldol Additions of Silyloxy Furans to Cyclic Ketones: Annulation of Butenolides and γ-Lactones Ke Kong and Daniel Romo* Department of Chemistry, Texas A&M UniVersity, P.O. Box 30012, College Station, Texas 77842-3012 romo@mail.chem.tamu.edu Received March 3, 2006 ABSTRACT Vinylogous Mukaiyama aldol reactions employing silyloxyfurans and substituted cyclic ketones are described. These annulations proceed with moderate to good diastereoselectivity. The potential application of this process to the synthesis of butenolide and γ-lactone containing natural products was demonstrated by further transformations of the addition products. The Mukaiyama aldol reaction is one of the most important carbon-carbon bond forming processes in an organic chemist’s repertoire. The vinylogous version of this process is an important extension and provides a concise entry to the δ-hydroxy-R,-unsaturated carbonyl motif (Scheme 1). 1 Furthermore, the addition of dienolsilanes to carbonyls or imines has been widely used in organic synthesis. 1 Consider- ing the significance of this process, it is surprising that there are only scant reports of dienolsilane additions to nonsym- metric ketones. 2 This is in sharp contrast with aldehydes which have been extensively explored as substrates for the vinylogous Mukaiyama aldol addition. 1a Presumably, low reactivity and low diastereoselectivity have hampered the use of ketones as electrophiles. 3 Because ketones are less reactive than aldehydes toward nucleophilic addition, highly elec- trophilic ketones, such as pyruvate esters, have been used for vinylogous Mukaiyama aldol reactions. 2b-d Because of the greater difficulty of differentiating diastereotopic faces of ketones compared to aldehydes, the addition of silyloxy- furans to aliphatic ketones proceeded with only moderate diastereoselectivity in the absence of external chiral ligands. 2a One solution to overcome this difficulty was the use of tetronic acid derived dianions. 4 In this case, a chelation- controlled process allowed the addition to proceed with good diastereoselectivity. (1) For recent reviews, see: (a) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. ReV. 2000, 100, 1929. (b) Denmark, S. E.; Heemstra, J. R.; Beutner, G. L. Angew. Chem., Int. Ed. 2005, 44, 4682. (c) Kalesse, M. Top. Curr. Chem. 2005, 244, 43. (2) (a) Jefford, C. W.; Jaggi, D.; Bernardinelli, G.; Boukouvalas, J. Tetrahedron Lett. 1987, 28, 4041. (b) Evans, D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S. W. J. Am. Chem. Soc. 1999, 121, 686. (c) Naito, S.; Escobar, M.; Kym, P. R.; Liars, S.; Martin, S. F. J. Org. Chem. 2002, 67, 4200. (d) Le, J. C.-D.; Pagenkopf, B. L. Org. Lett. 2004, 6, 4097. (3) (a) For a discussion of the low reactivity of ketones as electrophiles, see: Betancort, J. M.; Garcia, C.; Walsh, P. J. Synlett 2004, 749. (b) In a recent review of allylmetal additions to carbonyl compounds, only two pages were dedicated to ketones. See: Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763. Scheme 1. Vinylogous Mukaiyama Aldol Reaction ORGANIC LETTERS 2006 Vol. 8, No. 14 2909-2912 10.1021/ol060534q CCC: $33.50 © 2006 American Chemical Society Published on Web 06/15/2006